Womens Issues in Epilepsy Esther Bui, Epilepsy Fellow MD, FRCPC

How are women different?

Different habitus Different metabolism Different co-morbidities Different psychosocial stigma Different hormonal status

Catamenial seizures Pregnancy Menopause

Hormones and Epilepsy

Estradiol exerts direct excitatory effects at the neuronal

membrane by augments N methyl-D-aspartate (NMDA) mediated glutamate receptor activity

decreases inhibition by decreasing GABA synthesis

Logothetis et al. showed that intravenously administered conjugated estrogen activated epileptiform activity in 11/16 women, and associated with seizures in 4

PresenterPresentation NotesSeizure. 2008 Mar;17(2):151-9. Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Herzog AG.

Estradiol exerts direct excitatory effects at the neuronal membrane, where it augments Nmethyl- D-aspartate (NMDA) mediated glutamate receptor activity.11,12 This enhances the resting discharge rates of neurons in a number of brain areas, including the hippocampus1113 where estradiol increases excitability of the hippocampal CA1 pyramidal neurons and induces repetitive firing in response to Schaffer collateral stimulation.12 Estradiol potentiates neuronal excitability by regulating neuronal plasticity. It increases the density of spines and excitatory, NMDA receptor-containing synapses on the apical dendrites of hippocampal CA1 pyramidal neurons via a post-transcriptional mechanism.14,15 The dendritic spine density on these neurons correlates positively with thelevels of circulating estradiol during the estrous cycle of the rat and is decreased by oophorectomy. 14,15 Estradiol may thus further increase excitatory input to the CA1 neurons. Estradiol may affect neuronal excitability by cytosolic neuronal estrogen receptor-mediated, genomically dependent mechanisms. Receptors are particularly abundant in the temporolimbic system, especially in the medial and cortical amygdaloid nuclei, and occur in much fewer numbers in the hippocampal pyramidal cell layer and the subiculum. 16,17 Estrogen receptor-containing neurons colocalize with other neurotransmitters, including gamma-amino-butyric acid (GABA).18,19 By regulating the expression of genes affecting the activity, release and post-synaptic action of different neurotransmitters and neuromodulators, estrogens may act to increase the excitability of neurons, which concentrate estradiol. For instance, estradiol lessensinhibitory neurotransmission by decreasing GABA synthesis in the corticomedial amygdala by reducing the activity of glutamic acid decarboxylase, 20 and enhances brain epileptogenic muscarinic neurotransmission by increasing choline acetyl transferase and acetylcholine.21

11. Smith SS. Estrogen administration increases neuronal responses to excitatory amino acids as a long term effect. Brain Res 1989;503:3547.12. Wong M, Moss R. Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci 1992;12:321725.13. Kawakami M, Teresawa E, Ibuki T. Changes in multiple unit activity in the brain during the estrous cycle. Neuroendocrinol 1970;6:3048.14. Woolley CS, McEwen BS. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 1993;336:293306.15. Woolley CS, McEwen BS. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor- dependent mechanism. J Neurosci 1994;14:76807.16. Pfaff DW, Keiner M. Estradiol-concentrating cells in the rat amygdala as part of a limbic-hypothalamic hormone-sensitive system. In: Eleftheriou B, editor. The neurobiology of the amygdala. New York: Plenum Publishing; 1973. p. 77592.17. Simerly RB, Chang C, Muramatsu M, Swanson LW. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 1990;294:7695.18. McEwen BS. Nongenomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991;12:1417. 19. Finn DA, Gee KW. The influence of estrus cycle phase on neurosteroid potency at the GABAA receptor complex. J Pharmacol Exp Ther 1993;265:13749.20. Wallis CJ, Luttge WG. Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem 1980;34:60913.21. Luine VN, Renner KJ, McEwen BS. Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments. Endocrinology 1986;119:8748.

30. Logothetis J, Harner R, Morrell F, Torres F. The role of estrogens in catamenial exacerbation of epilepsy. Neurology (Minneap) 1959;9:35260.

Hormones and Epilepsy

Progesterone

progesterone, especially its neuroactive metabolite (allopregnanolone) exert direct membrane-mediated inhibitory effects by potentiating GABA A-mediated chloride conductance

also potentiates the action of the powerful endogenous

inhibitory substance adenosine

Backstrom et al. found that iv progesterone at sufficient doses was associated with decrease interictal spikes in 4/7 women with partial epilepsy

PresenterPresentation Notes9. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6: 231122.31. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232:10047.32. Gee KW, McCauley LD, Lan NC. A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons. Crit Rev Neurobiol 1995;9:20727.33. Phyllis JW. Potentiation of the depression by adenosine of rat cerebral cortex neurones by progestational agents. Br J Pharmacol 1986;89:693702.

Progesterone may act via genomic mechanisms to influence the enzymatic activity controlling the synthesis and release of various neurotransmitters and neuromodulators produced by progesteronereceptor-containing neurons.18 Progesterone binds specific cytosolic receptors not only to produce its own characteristic effects but also to lower estrogen receptor numbers and thereby antagonizeestrogen actions.35 Chronic progesterone decreases the number of hippocampal CA1 dendritic spines and excitatory synapses faster than the simple withdrawal of estrogen, counteracting the stimulatory effects of estradiol. 14 Progesterone and allopregnanolone have also been shown to have neuroprotective effects on hippocampal neurons in kainic acid-induced seizure models.36 In most adult female animal models, progesterone depresses neuronal firing,37 and lessens spontaneous and induced epileptiform discharges.2628,36 38 It retards kindling and decreases seizure occurrence. 2628,3638 Backstrom et al.39 found that intravenous infusion of progesterone, sufficient to produce luteal phase serum levels, was associated with a significant decrease in interictal spike frequency in four of seven women with partial epilepsy.

14. Woolley CS, McEwen BS. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 1993;336:293306.18. McEwen BS. Nongenomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991;12:1417.26. Nicoletti F, Speciale C, Sortino MA, Summa G, Caruso G, Patti F, et al. Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats. Epilepsia 1985;26:2527.27. Spiegel E, Wycis H. Anticonvulsant effects of steroids. J Lab Clin Med 1945;30:94753. 28. Woolley DE, Timiras PS. The gonadbrain relationship: effects of female sex hormones on electroshock convulsions in the rat. Endocrinology 1962;70:196209.36. Frye CA. The neurosteroid 3a-5a-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res 1995;696:11320.37. Smith SS, Waterhouse BD, Woodward DJ. Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters. Brain Res 1987;422:52 62.38. Landgren S, Backstrom T, Kalistratov G. The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cats cerebral cortex. J Neurol Sci 1978;36:11933.39. Backstrom T, Zetterlund B, Blom S, Romano M. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 1984;69:2408.

Estrogen Proconvulsant

Progesterone Anticonvulsant

Epilepsy and Fertility Issues

Epilepsy and Fertility

Decreased fertility among women with epilepsy (II)

Polycystic Ovarian Disease Sexual Dysfunction Psychosocial effect of epilepsy AED effect to the fetus Effect of seizures for the fetus

AED and OCP interactions

Polycystic Ovarian Disease (PCOS) Failure of the ovarian follicle to complete normal maturation during

the menstrual cycle Syndrome of

hyperandrogenism (raised testosterone levels) multiple ovarian cysts anovulatory cycles hirsutism obesity

Prevalence of PCOS in women without epilepsy is between 4% -6% in women with epilepsy unknown (~ 2 x that of women without epilepsy),

even in those not taking AED medication* more common in women taking valproate, especially if started < age 20

PresenterPresentation NotesBetts T, Crawford P. Women and Epilepsy. London, UK: Martin Dunitz, 1998:pp.278.Isojarvi JIT, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:57984.Isojarvi JIT, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329:13838.Herzog AG. Reproductive endocrine regulation in men with epilepsy: effects on reproductive function and neuronal excitability. Ann Neurol 2002;51:53942.Herzog AG, Coleman AE, Jacobs AR, et al. Interictal EEG discharges, reproductive hormones and menstrual disorders in epilepsy. Ann Neurol 2003;54:62537.

AEDs and OCPs

Increased breakthrough bleeding noticed when dosing of OCP decreased from 50-100ug to < 50 ug (due to risk of thrombosis)

Modern available combined OCPs contain

2035 ug of ethinylestradiol and < 1 mg of progestogen

Lamotrigine* - cOCP can decrease lamotrigine trough levels by 2570% AND - 20% to 100% of progestogen-only oral contraceptive Benzodiazepines - no effect on OCP

For women on enzyme-inducing AEDs wishing to take OCPs

cOCP Start with 50 g/day ethinyl oestradiol dosage (C) If breakthrough bleeding occurs, increase the dose of ethinyl oestradiol to 75

or 100 g/day (C)

Other contraceptive methods Medroxyprogesterone injections effective (III) but take q10 weeks rather than

12 weeks if using enzyme-inducing AEDs IUDs also effective (acts locally) Emergency contraceptive pill can be used in women with epilepsy after

unprotected sexual intercourse (C)

Ineffective Progesterone only pill (III) Levonorgestrel implants - high failure rate (III)

Should always recommend second contraceptive methods

PresenterPresentation NotesEven on a higher-dose COCP with normal cycles, full oral contraceptive efficacy cannot be guaranteed while taking enzyme-inducing AEDs (III)No contraindications to the Mirena coil (III)

Catamenial Seizures

Catamenial Seizures

Doubling of seizures around menses Occurs in about 12% of women with epilepsy (II) Can affect ~ 1/3 of women with localization-related epilepsy

3 catamenial seizure patterns have been identified

Ovulatory cycles During perimenstrual days (pattern C1) Periovulation (pattern C2)

Anovulatory cycles Post-ovulation, when luteal phase inadequate (pattern C3)

PresenterPresentation NotesHerzog AG, Harden CL, Liporace J, et al. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Ann Neurol 2004;56(3):4314.

Herzog AG, Klein P, Ransil B. Three patterns of catamenial epilepsy. Epilepsia 1997;38:10828.

Ovulatory Cycles

Seizure frequency shows positive correlation with serum estradiol/progesterone ratio

Ratio is highest during days prior to ovulation and menstruation and is lowest during the early and midluteal phase (post-ovulatory)

Premenstrual exacerbation of seizures has been

attributed to the rapid withdrawal of the antiseizure effects of progesterone

PresenterPresentation NotesBackstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54:32147.Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:10828.Herzog AG. Progesterone therapy in complex partial and secondary generalized seizures. Neurology 1995;45:16602.Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999;52:19178.Herzog AG. Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders. Neurology 1986;36:160710.

Herzog et al. [47] presented statistical evidence to support the concept of catamenial epilepsy and the existence of at least three distinct patterns of seizure exacerbation in relation to the menstrual cycle: (1) perimenstrual (C1: Days 3 to 3) and (2) periovulatory (C2: Days 10 to 13) in normal cycles, and (3) luteal (C3: Days 10 to 3) in inadequate luteal phase cycles. In these cycles, Day 1 is the first day of menstrual flow and ovulation is presumed to occur 14 days before the subsequent onset of menses (Day 14). These three patterns can be demonstrated by (1) charting menses and seizures and (2) obtaining a midluteal phase serum levels. Two open-label trials of adjunctive progesterone therapy for women with catamenial epilepsy did result in clinically important and statistically significant reductions in seizure occurrence [49,50]. Progestogen treatment has taken two forms: (1) cyclic progesterone therapy that supplements progesterone during the luteal phase and withdraws it gradually premenstrually, and (2) suppressive therapy in which the goal is to suppress the menstrual cycle which is generally accomplished using injectable progestins or GnRH analogs [51]. Oral synthetic progestins administered cyclically or continuously have not proven to be an effective therapy for seizures in clinical investigations [52], although individual successes with continuous daily oral use of norethistrone and combination pills have been reported [53].

[47] Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:10828.[48] Herzog AG, Harden CL, Liporace J, et al. Frequency of catamenial seizureexacerbation in women with localization-related epilepsy. Ann Neurol 2004;56:4314.[49] Herzog AG. Progesterone therapy in complex partial and secondary generalized seizures. Neurology 1995;45:16602. [50] Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999;52:19178.[51] Herzog AG. Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders. Neurology 1986;36:160710.[52] Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology (Cleve)1984;34:12558.[53] Hall SM. Treatment of menstrual epilepsy with a progesterone-only oral contraceptive. Epilepsia 1977;18:2356.

Ovulatory Cycle

PresenterPresentation NotesFigure 1 Three patterns of catamenial epilepsy: perimenstrual (C1) and periovulatory (C2) exacerbations duringnormal ovulatory cycles and entire second half of the cycle (C3) exacerbation during inadequate luteal phase cycleswhere Day 1 is the first day of menstrual flow and Day 14 is the day of ovulation.

Seizure. 2008 Mar;17(2):151-9. Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Herzog AG.

Anovulatory Cycle

Catamenial Seizures

Catamenial seizure exacerbations primarily related to changing sex hormone concentrations during the menstrual cycle

But also alterations in AED concentrations,

as seen with phenytoin and lamotrigine, throughout the menstrual cycle

PresenterPresentation NotesBackstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54:32147.Neme SB, Foldvary-Schaefer NR. Lamotrigine concentrations across the menstrual cycle in women with catamenial epilepsy. Epilepsia 2004;45(suppl 7):125.Rosciszewska D, Buntner B, Guz I, et al. Ovarian hormones, anticonvulsant drugs and seizures during the menstrual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry 1986;49:4751.Kumar G, Behari M, Ahuja GK, et al. Phenytoin levels in catamenial epilepsy. Epilepsia 1988;29:1558.Shavit G, Lerman P,Korczyn AD, et al. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 1984;34:95961.

Catamenial Seizures Treatment Strategies

AED dose around time of seizures

Avoid cyclic variation by a continuous OCP Supplemental progesterone during luteal phase

Double-blind, randomized, placebo-controlled trial of

cyclic supplemental progesterone currently underway

PresenterPresentation NotesPennell PB. 2005 AES annual course: evidence used to treat women with epilepsy. Epilepsia 2006;47(Suppl. 1):4653.

Herzog AG. Catamenial epilepsy: definition, prevalence, pathophysiology and treatment. Seizure 2008;17(2):1519.

Catamenial Seizures Treatment Strategies

For women already on AEDs intermittent clobazam on days when seizures (B) acetazolamide perimenstrually (C) progestogens perimenstrually (C)

For women not already taking AEDs intermittent perimenstrual clobazam (5 to 30 mg/day) COCP; depot progestogen therapy; or perimenstrual

progestogen (III)

Pregnancy and Epilepsy

Pregnancy and Epilepsy

> 90% of women with epilepsy have a normal pregnancy Obstetrical risks of pregnancy inconclusive

low birth weight preeclampsia bleeding placental abruption prematurity neonatal or perinatal death reported 2-3x higher, though wide

variability in studies, including one study with no increased risk of death*

No increased risk of major fetal malformation

PresenterPresentation NotesCommunity-based, Prospective, Controlled Study of Obstetric and Neonatal Outcome of 179 Pregnancies in Women with Epilepsy. AUViinikainen K; Heinonen S; Eriksson K; Kalviainen R SOEpilepsia. 2006 Jan;47(1):186-92. Summary: Purpose: This study evaluated obstetric and neonatal outcome in a community-based cohort of women with active epilepsy (WWAE) compared with the general pregnant population receiving modern obstetric care. Methods: We reviewed the total population who gave birth between January 1989 and October 2000 at Kuopio University Hospital. Obstetric, demographic, and epilepsy data were collected prospectively from 179 singleton pregnancies of women with epilepsy and from 24,778 singleton pregnancies of unaffected controls. The obstetric data from the pregnancy register was supplemented with detailed neurologic data retrieved from the medical records. The data retrieved were comprehensive because of a follow-up strategy according to a predecided protocol. Results: During pregnancy, the seizure frequency was unchanged, or the change was for the better in the majority (83%) of the patients. We found no significant differences between WWAE and controls in the incidence of preeclampsia, preterm labor, or in the rates of caesarean sections, perinatal mortality, or low birth weight. However, the rate of small-for-gestational-age infants was significantly higher, and the head circumference was significantly smaller in WWAE. Apgar score at 1 min was lower in children of WWAE, and the need for care in the neonatal ward and neonatal intensive care were increased as compared with controls. The frequency of major malformations was 4.8% (-0.6-10.2%; 95% confidence interval) in the 127 children of WWAE. Conclusions: Pregnancy course is uncomplicated and neonatal outcome is good in the majority of cases when a predecided protocol is used for the follow-up of WWAE in antenatal and neurologic care. Long-term follow-up of the neurologic and cognitive development of the children of WWAE is still needed. ADDepartment of Neurology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland.

Pregnancy and Epilepsy Most women will have no change of their seizure pattern

during pregnancy (~50%), 25% will have improved seizure frequency

Factors that may exacerbate seizures

noncompliance nausea and vomitting inappropriate decrease in AED changes in blood volumes sleep deprivation

If a patient has been seizure free for at least 2 3 years with no risk factors for seizure recurrence, consider withdrawing AEDs 6 months prior to planned conception

Pregnancy and Anticonvulsants Increased risk of fetal malformations with intrauterine

exposure to 4 major anticonvulsants Phenytoin Carbemazepine Valproic acid Phenobarbital

Major fetal malformations is 4-6% vs 2-3% Most studies identify valproate (~7-10%) or polytherapy

(15%) exposure as the highest risk, especially in first trimester*

PresenterPresentation NotesMinor malformations: dysmorphic features (generally considered minor malformations) associated with the administration of AEDs is also not clear [29,30]. Many of these drugs appear to be implicated in dysmorphisms such as hypoplasia of the nails and distal phalanges, hypertelorism, and the "anticonvulsant face" (broad or depressed nasal bridge, short nose with anteverted nostrils, long upper lip, maxillary hypoplasia)

Major malformations: cleft palate, spina bifida aperta, open lumbosacral myelocele), cardiac, urogenital

Nakane Y, Okuma T, Takahishi R, et al. Multi-institutional study on the teratogenicity and fetal toxicity of anticonvulsants: a report of a collaborative study group in Japan. Epilepsia 1980;21:66380.Morrow J, Craig J. Epilepsy, pregnancy and the advent of pregnancy registers. Prog Neurol Psychiatry 2004;248.Vajda FJ, OBrien TJ, Hitchcock A, et al. Australian pregnancy register of women on antiepileptic drugs: 5-year results. Epilepsia 2004;45(suppl 7):234.

Pregnancy and Anticonvulsants

Valproic Acid 1-2% of babies with neural tube defects (10-20x) Major birth defects in VPA monotherapy 10.7% vs 2.9% for other AEDs Dose related

1000 mg/day OR ~ 1 1500 mg/day OR = 3.7 >1500 mg/day OR = 10.9*

Lamotrigine Best studied newer AED ~3% incidence of major malformations with 1st trimester exposure North American AED Pregnancy Registry noted a higher than expected

prevalence of cleft palate and/or cleft lip (not reproduced)

PresenterPresentation Notes*Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. AUArtama M; Auvinen A; Raudaskoski T; Isojarvi I; Isojarvi J SONeurology 2005 Jun 14;64(11):1874-8. OBJECTIVE: To compare the risk for congenital malformations in offspring between women with epilepsy being treated with antiepileptic drugs (AEDs) during pregnancy and those who discontinued their antiepileptic medication before pregnancy in a population-based cohort of female patients with epilepsy. METHODS: All patients with epilepsy (n = 20,101) eligible for AED reimbursement for the first time during 1985 to 1994 were identified from the Social Insurance Institution of Finland. Information on births during 1991 to 2000 was obtained from the National Medical Birth Registry. Information on AED use during pregnancy and on pregnancy outcomes was abstracted from medical records. RESULTS: Congenital malformations were more common among offspring of women on antiepileptic medication (65/1,411; 4.6%) than among offspring of untreated patients (26/939; 2.8%) (p = 0.02). The risk of malformations was substantially higher in the offspring of patients using valproate as monotherapy (OR = 4.18; 95% CI: 2.31, 7.57) or valproate as polytherapy (OR = 3.54; 95% CI: 1.42, 8.11) than of untreated patients. Polytherapy without valproate was not associated with increased risk of malformations. CONCLUSION: Excess risk was confined to patients using valproate during pregnancy. The risk for malformations was not elevated in offspring of mothers using carbamazepine, oxcarbazepine, or phenytoin (as monotherapy or polytherapy without valproate). Finland

Longterm effects of AED exposure

Intrauterine exposure to valproate resulted in children with IQ scores ~ 6-9 points lower than those exposed to other AED (lamotrigine, phenytoin, or carbamazepine)

No specific dose response established

PresenterPresentation Notes*Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantre D,Cohen M, Kalayjian L, Kanner A, Liporace J, Pennell P, Privitera M,Loring D. (2008b) Neurodevelopmental effects of fetal antiepilepticdrug exposure: 3 year old cognitive outcomes. Epilepsia 49:489.

Post-partum

1-2% of women with active epilepsy will have a tonicclonic seizure during labor

Further 12% will have a seizure within 24 h* If AED dose increased during pregnancy,

gradually reduce it to preconception dose over the few weeks following delivery, to reduce the risk of maternal drug toxicity

PresenterPresentation NotesIf a corticosteroid is necessary due to premature labor, women taking hepatic microsomal enzyme-inducing AEDs will need an increased corticosteroid dose to try to prevent respiratory distress syndrome in the babyBardy A. Epilepsy and Pregnancy, A Prospective Study of 154 Pregnancies in Epileptic Women. Helsinki, Finland: University of Helsinki, 1982.

Breastfeeding and AEDs

Any theoretical risks need to be balanced against the known benefits of breastfeeding,

psychological benefits for mother and child reduced infant mortality fewer infectious disease decreased risk of immunologically mediated disorders (type 1 DM)*

Current recommendations all support breastfeeding Watch for lethargy (especially with benzodiazepines, barbituates) Lamotrigine

Increased risk of toxicity Suggest lamotrigine levels should be monitored in breastfed children

whose mothers are taking high-dose lamotrigine

PresenterPresentation NotesBreastfeeding and the use of human milk. American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeed Rev 1998;6(1):316.

Recommendations AED therapy should be optimized prior to conception (monotherapy

preferred) No agreement to which AED is most or least teratogenic AED that stops seizures in a given patient is the one that should be used

(VPA*) Plasma drug level should be monitored regularly during pregnancy (free drug

levels more reliable) Screen for neural tube defects, specialized OB centre

Folic acid daily prior to conception Vitamin K (20 mg/day po) in last month, infants should receive 1mg

IM at birth Breast feeding recommending even while on AED

PresenterPresentation Notesdrug metabolism, including increased liver metabolism, renal clearance, and volume of distribution, and decreased gastrointestinal absorption and plasma protein binding

Epilepsy and Menopause

Epilepsy and Menopause

Epilepsy can alter timing of menopause*

Association between partial epilepsy and premature menopause

Relationship between seizure frequency and age at menopause

Increased frequency of premature ovarian failure in women with epilepsy

PresenterPresentation NotesHerzog AG, Seibel MM, Schomer DL, et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:3416.Harden CL, Koppel BS, Herzog AG, Nikolov BG, Hauser WA. Seizure frequency is associated with age at menopause in women with epilepsy. Neurology 2003;61:4515. OBJECTIVE: To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. METHODS: Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. RESULTS: Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. CONCLUSIONS: Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.

Klein P, Serje A, Pezzulo JC. Premature ovarian failure in women with epilepsy. Epilepsia 2001;42:15849.Good review paper (especially on catamenial epilepsy and menopause) Epilepsy Behav. 2009 May;15(1):78-82. Female issues in epilepsy: a critical review. Luef G.

Epilepsy and Menopause

Small survey studies report seizures during the perimenopausal transition, but improved seizure frequency once menopause complete*

Catamenial epilepsy pattern a hallmark for the observed increase at perimenopause but decrease at menopause

Multicenter, randomized, placebo-controlled trial in postmenopausal women with epilepsy demonstrated seizure frequency in a dose-dependent fashion with HRT (Prempro, conjugated equine estrogens plus medroxyprogesterone acetate)*

PresenterPresentation NotesPennell PB. 2005 AES annual course: evidence used to treat women with epilepsy. Epilepsia 2006;47(Suppl. 1):4653.Abbasi F, Krumholz A, Kittner SJ, et al. Effects of menopause on seizures in women with epilepsy. Epilepsia 1999;40(2):20510.Harden CL, Pulver MC, Ravdin L, et al. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999;40(10):14027.Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study. Epilepsia 2006;47(9):144751.

Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study.Harden CL, Herzog AG, Nikolov BG, Koppel BS, Christos PJ, Fowler K, Labar DR, Hauser WA.Comprehensive Epilepsy Center, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA. clharden@med.cornell.eduPURPOSE: Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency. METHODS: This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. RESULTS: Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25-30% while taking CEE/MPA. CONCLUSIONS: CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.

Epilepsy and Menopause

During menopause seizure frequency Worsens in ~ 40% Improves in ~30% No change in ~ 30%*

HRT significantly seizure frequency

during menopause, more likely in women with history of catamenial epilepsy

PresenterPresentation NotesEpilepsia. 2005;46 Suppl 9:117-24. Best practice guidelines for the management of women with epilepsy. Crawford P.

Epilepsy and Bone Health Women with epilepsy at risk of fractures, osteoporosis, and

osteomalacia ~10% of women with epilepsy have premature bone demineralization,

especially if using AEDs that induce the hepatic cytochrome P450 enzyme system

Multifactorial

Adverse effects of AEDs on bone metabolism, vitamin D, bone turnover Trauma of seizures Subtle effects of AEDs on coordination

Most effective therapy for AED-induced osteoporosis has not been

established

PresenterPresentation NotesHarden CL. Menopause and bone density issues for women with epilepsy. Neurology 2003;61:S1622.Elliott JO, Darby JM, Jacobson MP. Bone loss in epilepsy: barriers to prevention, diagnosis, and treatment. Epilepsia 2004;45(suppl 7):258.

PresenterPresentation NotesCleve Clin J Med. 2004 Feb;71 Suppl 2:S49-57. Recommendations for the care of women with epilepsy. Penovich PE, Eck KE, Economou VV.

Recommendations

Screening with bone scans of the spine or hip should be obtained in at-risk women and be repeated every 2 years or if a fracture occurs

Women should be counseled about adequate

calcium intake, and a dietary history should be obtained

Supplementation with calcium and vitamin D

Conclusions

Women with epilepsy have unique issues Fertility Catamenial seizures Pregnancy Menopause Bone Health

Thank you!

Womens Issues in EpilepsyHow are women different?Slide Number 3Hormones and EpilepsyHormones and EpilepsySlide Number 7Epilepsy and Fertility IssuesEpilepsy and FertilityPolycystic Ovarian Disease (PCOS)AEDs and OCPsSlide Number 12For women on enzyme-inducing AEDs wishing to take OCPsCatamenial SeizuresCatamenial SeizuresOvulatory CyclesOvulatory CycleAnovulatory CycleCatamenial SeizuresCatamenial Seizures Treatment StrategiesCatamenial Seizures Treatment StrategiesPregnancy and EpilepsyPregnancy and EpilepsyPregnancy and EpilepsyPregnancy and AnticonvulsantsPregnancy and AnticonvulsantsLongterm effects of AED exposurePost-partumBreastfeeding and AEDsRecommendationsEpilepsy and MenopauseEpilepsy and MenopauseEpilepsy and MenopauseEpilepsy and MenopauseEpilepsy and Bone HealthSlide Number 38RecommendationsConclusionsThank you!